The complement system comprises a complex array of enzymes and non-enzymatic proteins of importance to the function of the innate as well as the adaptive immune defenses1. Until recently two modes of activation were known, the classical pathway initiated by antibody-antigen complexes and the alternative pathway initiated by certain structures on microbial surfaces. A third, novel antibody-independent pathway of complement activation has been described2. This pathway is initiated when mannan-binding lectin (MBL, first described as mannan-binding protein, MBP, see Ezekowitz, U.S. Pat. No. 5,270,199) binds to carbohydrates.
MBL is structurally related to the Clq subcomponent of component Cl of complement, and it appears that MBL activates the complement system via an associated serine protease termed MASP4 or p1005, which is similar to the Clr and Cls components of the classical pathway. The new complement activation pathway is called the MBLectin pathway. According to the mechanism postulated for this pathway, MBL binds to specific carbohydrate structures found on the surface of a range of microorganisms including bacteria, yeast, parasitic protozoa and viruses6, and its antimicrobial activity results from activation of the terminal, lytic complement pathway components7 or promoting phagocytosis8.
Reportedly, the level of MBL in plasma may be genetically determined9,10,11. MBL deficiency is associated with susceptibility to frequent infections with a variety of microorganisms in childhood12,13 and, possibly, in adults13,14. Recent information associates MBL deficiency with HIV infection and with more rapid death following development of AIDS15,16. MBL binds to the a galactosyl form of IgG (G0), which is found at elevated concentrations in rheumatoid arthritis patients, and then activates complement17. MBL deficiency is also associated with a predisposition to recurrent spontaneous abortions18, and also to development of systemic lupus erythrematosus19.
In the first clinical reconstitution trial, an infant MBL-deficient girl suffering from recurrent infections was apparently cured by injections with purified MBL20. For a recent review on MBL, see ref. 6.
Relatively high frequencies of MBL mutations associated with MBL-deficiency have been reported in all populations studied. This observation has led to the hypothesis that MBL may, in certain cases, render the individual more susceptible to certain intracellular infectious agents exploiting MBL to gain access to the target tissues21. Since MBL is a very powerful activator of the complement system, it may also be that inexpedient activation through microbial carbohydrates or endotoxins can lead to damaging inflammatory responses10. Thus, the overall survival of a population may benefit from the wide individual range of MBL concentrations.
MASP-1 (MBP-associated serine protease, MASP) is a serine protease similar in structure to Clr and Cls of the complement pathway although it has a histidine loop structure of the type found in trypsin and trypsin-like serine proteases. MASP-1 has been found to be involved in complement activation by MBL. A cDNA clone encoding MASP-1 has been reported that encodes a putative leader peptide of 19 amino acids followed by 680 amino acid residues predicted to form the mature peptide.
An abstract reports the existence of a second MASP, termed MASP-2.22.